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Preclinical data have suggested that the bile acid Ursodeoxycholic acid (or UDCA) has neuroprotective properties in models of Parkinson’s.
Researchers in Sheffield have led much of this research and they have also been coordinating a clinical trial assessing this molecule in people with Parkinson’s.
The study was called the “UDCA in Parkinson’s” trial (or UP Study) and the results were recently published.
In today’s post, we will explore the history of UDCA research, review the results of the UP study, and discuss what could happen next.
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Prof Heather Mortiboys. Source: Dementiaresearcher
Every good lab bench-to-clinical trial story starts somewhere.
There is an initiating moment, which is probably irrelevant to most of the people present at the time, but it becomes life-defining for others. In the case of today’s post, that moment occurred while Prof Heather Mortiboys was was sitting in a lecture during the last year of her undergraduate degree in University.
The lecturer said that although our knowledge and understanding of what happens in Parkinson’s has increased significantly, there are still no treatments to prevent or slow the condition.
Heather couldn’t understand this.
She wondered how much more knowledge could be gained without actually identifying new treatments? And from that moment onwards she has pursued a research career in Parkinson’s research (and we are lucky for it!).
After receiving her PhD in Neuroscience (summa cum laude) from the International Max Planck Institute in Dresden (Germany), she moved to the Neuroscience department at the University of Sheffield in 2006 to work with Prof Oliver Bandmann.
Prof Oliver Bandmann. Source: Sheffield
And in 2013, they published the results of a large screening study that identified a very interesting molecule.
This was the research report in question:
Title: Ursocholanic acid rescues mitochondrial function in common forms of familial Parkinson’s disease
Authors: Mortiboys H, Aasly J, Bandmann O.
Journal: Brain. 2013 Oct;136(Pt 10):3038-50.
What was the interesting molecule?
In their study, the investigators took 2000 drugs (including 1040 licensed drugs and 580 naturally occurring compounds) and screened the agents for their ability to rescue mitochondrial dysfunction.
What is mitochondrial dysfunction?
Mitochondria small bean shaped structures inside of cells. They are the power house of each cell, providing them with energy, which helps to keep the lights on. Without mitochondria, the lights go out and the cell dies.
Mitochondria and their location in the cell. Source: NCBI
There are genetic risk factors associated with Parkinson’s. They are carried by approximately 15-20% of people affected by PD. Curiously, some of those genetic risk factors are associated with mitochondrial function. In particular, some of them are related to the process of disposing of old/dysfunctional mitochondria. One of those genetic risk factors involves tiny errors (or variations) in a section of DNA called the PARK2 gene (also known as PARKIN – click here to read a previous SoPD post related to this). In cells with PARK2 genetic variants, old and dysfunctional mitochondria are not disposed of correctly which causes cellular stress.
In their huge screen of 2000 drugs, the researchers in Sheffield used skin cells (called fibroblasts) from people with PARK2/PARKIN genetic mutations for their study. They identified 15 drugs that could rescue the mitochondria dysfunction in the PARK2 skins cells. Of those 15 compounds, two were chosen for further functional analysis. They were:
- Ursocholanic acid
- Dehydro(11,12)ursolic acid lactone
Neither ursocholanic acid nor dehydro(11,12)ursolic acid lactone are FDA-licensed drugs. In fact, we have little if any information regarding their use in humans. Given this situation, the researchers turned their attention to a molecule chemically related to ursocholanic acid.
That molecule was ursodeoxycholic acid:
Ursocholanic acid vs UDCA. Source: Wikipedia
What is ursodeoxycholic acid?
Ursodeoxycholic acid (simply abbreviated to UDCA; also known as ursodiol) is a bile acid. It is a naturally occurring molecule that changes the composition of bile and helps to dissolve gallstones.
UDCA was first discovered in bears, hence the use of the root-word for ‘bear’ (urso-) in its name.
Cute, but don’t get too close. Source: Constantinealexander
Remind me again: What is a bile acid?
Bile is a fluid that is made and released by the liver and stored in the gallbladder. It contains bile acids which are used for two main purposes: First, in the breakdown and absorption of fats and vitamins from food as they pass through the gut. The second purpose of bile is to aid with the removal of waste products.
Bile. Source: Osmosis
Bile acids are made in the liver, stored in the gallbladder and released into the small intestine when food is eaten. Virtually all (>95%) of the bile acids are re-absorbed in the final section of the small intestine and returned to the liver.
Ok, so how might a bile acid help with Parkinson’s?
Back in 1994, some researchers reported something very interesting about UDCA:
Title: Ursodiol for the long-term treatment of primary biliary cirrhosis. The UDCA-PBC Study Group.
Authors: Poupon RE, Poupon R, Balkau B
Journal: N Engl J Med. 1994 May 12;330(19):1342-7.
PMID: 8152446 (This article is OPEN ACCESS if you would like to read it)
In this study the researchers were looking for a new therapy for primary biliary cirrhosis.
Primary biliary cirrhosis is a liver disease. It is an autoimmune condition (meaning that your immune system starts to attack your body) which causes a slow, progressive destruction of the bile ducts of the liver, resulting in the build up of bile and other toxins in the liver.
Given that ursodiol (UDCA) is not toxic to liver cells in humans, the researcher hypothesised that long-term treatment with this drug might help displace the build up of bile acids and thus reduce their toxicity in primary biliary cirrhosis.
And guess what: It worked!
The investigators recruited and randomly assigned 145 patients with biopsy-proved primary biliary cirrhosis to receive either ursodiol (72 patients) or a placebo (73 patients) for 2 years. They found that long-term ursodiol therapy slowed the progression of the condition and reduced the need for liver transplantation.
Interesting, but what about Parkinson’s?
Well, additional studies found that this ‘rescue effect’ may actually be partly due to cellular protective mechanisms rather than simply displacing the build up of other bile acids. Additional studies indicated that UDCA has protective properties, characterised by the blocking of cell death.
One example is this report:
Title: A novel role for ursodeoxycholic acid in inhibiting apoptosis by modulating mitochondrial membrane perturbation
Authors: Rodrigues CM, Fan G, Ma X, Kren BT, Steer CJ
Journal: J Clin Invest. 1998 Jun 15;101(12):2790-9.
PMID: 9637713 (This article is OPEN ACCESS if you would like to read it)
In this study, the researchers found that UDCA treatment in both hepatocytes and non-liver cells could block apoptosis (or programmed cell death). Apoptosis occurs when a cell is sick or damaged and it decides to shut down and die, initiating a programme of self destruction.
The investigators exposed liver cells to a range of apoptosis-inducing agents (from toxic doses of chemicals to apoptosis-causing proteins), and they found that co-administration of UDCA with each of these was associated with a 50-100% inhibition of apoptotic changes. They concluded that their “results suggest that UDCA plays a central role in modulating the apoptotic threshold” of the cells they tested.
I’m still waiting for a connection to Parkinson’s. Are we getting close?
We have arrived.
Subsequent to these previous studies, research groups have observed similar beneficial effects with UDCA in models of Parkinson’s:
Title: Ursodeoxycholic acid suppresses mitochondria-dependent programmed cell death induced by sodium nitroprusside in SH-SY5Y cells.
Authors: Chun HS, Low WC.
Journal: Toxicology. 2012 Feb 26;292(2-3):105-12.
In this study, the researchers demonstrated that UDCA could protect dopamine cells grown in cell culture from apoptosis, and they also found that UDCA is doing this by regulating specific cell survival pathways (PI3K-Akt/PKB).
And this brings us back to the researchers in Sheffield.
Ok, so the researchers in Sheffield tested UDCA on their cells and what did they find?
When the researchers tested UDCA on PARK2 skin cells, and they found that it too rescued the mitochondrial function in those cells.
The researchers next tested UDCA on skin cells from people with Parkinson’s who had mutations in another Parkinson’s-associated gene, LRRK2 (also known as PARK8). We have discussed LRRK2 a lot on this website (Click here for a previous SoPD post on this topic), but Prof Mortiboys and her Sheffield colleagues had previously found impaired mitochondrial function and morphological issues in skin cells taken from people with LRRK2-associated Parkinson’s (Click here to read more about this), and other groups had reported similar findings (Click here for more on this).
Can you guess what happened when they treated the PARK8 cells with UDCA?
UDCA was able to rescue the mitochondrial effect in those cells as well?
And the researchers in Sheffield have also demonstrated that UDCA can also correct mitochondrial dysfunction in skin cells for people with Alzheimer’s-associated genetic variants (Click here to read more about this).
Obviously, these results excited the scientists and they set up a collaboration with researchers at York University (UK) and from Trondheim (Norway), to look at the potential of UDCA in rescuing the fate of LRRK2 flies.
The results of that study were published in this report:
Title: UDCA exerts beneficial effect on mitochondrial dysfunction in Lrrk2 (G2019S) carriers and in vivo.
Authors: Mortiboys H, Furmston R, Bronstad G, Aasly J, Elliott C, Bandmann O.
Journal: Neurology. 2015 Sep 8;85(10):846-52.
PMID: 26253449 (This article is OPEN ACCESS if you would like to read it).
The researchers tested UDCA on flies (or drosophila) with specific PARK8/LRRK2 mutations (G2019S) display a progressive loss of photoreceptor cell function in their eyes. The mitochondria in the photoreceptor cells are swollen and disorganised. When the investigators treated the flies with UDCA, they found approximately 70% rescue of the photoreceptor cells function.
The researchers in Sheffield concluded that UDCA has a marked rescue effect on cells from a Parkinson’s-associated gene mutation model, and they proposed that “mitochondrial rescue agents may be a promising novel strategy for disease-modifying therapy in LRRK2-related PD, either given alone or in combination with LRRK2 kinase inhibitors” (Click here to read a previous post on the topic of LRRK2 inhibitors).
And this study was followed by another report (from an independent research group) which involved testing UDCA in rodent models of Parkinson’s:
Title: Ursodeoxycholic Acid Ameliorates Apoptotic Cascade in the Rotenone Model of Parkinson’s Disease: Modulation of Mitochondrial Perturbations.
Authors: Abdelkader NF, Safar MM, Salem HA.
Title: Mol Neurobiol. 2016 Mar;53(2):810-7.
These researchers found UDCA rescued a rodent model of Parkinson’s (involving the neurotoxin rotenone). UDCA not only improved mitochondrial performance in the rats, but also demonstrated anti-inflammatory and anti-cell death properties.
The group in Sheffield have also investigated the use of UDCA in other neurodegenerative conditions, and that work has highlighted the potential use of UDCA to treat Alzheimer’s:
Title: Ursodeoxycholic Acid Improves Mitochondrial Function and Redistributes Drp1 in Fibroblasts from Patients with Either Sporadic or Familial Alzheimer’s Disease.
Authors: Bell SM, Barnes K, Clemmens H, Al-Rafiah AR, Al-Ofi EA, Leech V, Bandmann O, Shaw PJ, Blackburn DJ, Ferraiuolo L, Mortiboys H.
Journal: J Mol Biol. 2018 Oct 19;430(21):3942-3953.
PMID: 30171839 (This report is OPEN ACCESS if you would like to read it)
In this study, Prof Mortiboys and colleagues reported that skin cells (fibroblasts) from individuals with Alzheimer’s (both sporadic and cases associated with a genetic variation in the PSEN1 gene) share similar impairments in mitochondrial function and changes in mitochondrial morphology. They also noted that UDCA treatment was able to rescue both of these features.
Interestingly, the investigators found that removing the actions of a protein called dynamin-related protein 1 (or Drp1) abolished the protective effect of UDCA, providing interesting mechanistic insights into the actions of UDCA. Previous Parkinson’s-related research suggests that the pathological actions of alpha synuclein are associated with reduced levels of mitochondrial Drp1 (Click here and here to read more about this) and Drp1 has been implicated in cases of Parkinson’s associated with variations in the PINK1 gene (Click here to read more about this).
More recently, the Sheffield research team (in collaboration with researchers in Oxford) published another study assessing UDCA in models of Parkinson’s:
Title: Deep phenotyping of peripheral tissue facilitates mechanistic disease stratification in sporadic Parkinson’s disease.
Authors: Carling PJ, Mortiboys H, Green C, Mihaylov S, Sandor C, Schwartzentruber A, Taylor R, Wei W, Hastings C, Wong S, Lo C, Evetts S, Clemmens H, Wyles M, Willcox S, Payne T, Hughes R, Ferraiuolo L, Webber C, Hide W, Wade-Martins R, Talbot K, Hu MT, Bandmann O.
Journal: Prog Neurobiol. 2020 Apr:187:101772.
PMID: 32058042 (This report is OPEN ACCESS if you would like to read it)
In this study, the researchers collected skin cells (fibroblasts) from 100 people with Parkinson’s and from 50 age-matched control people without Parkinson’s
Fibroblasts are very robust and easy to grow in cell culture, and as such they represent a useful and accessible means of personalising medicine. By taking a simple skin biopsy, researchers can grow cells in culture from a specific person with Parkinson’s and conduct various tests or administer particular treatments to explore the characteristics of that person’s Parkinson’s.
Fibroblasts growing in culture. Source: Wikipedia
The researchers in Sheffield & Oxford were interested in assessing whether they could use fibroblasts to better subtype people with Parkinson’s.
What do you mean by subtype?
If you go along to any Parkinson’s support group, you will see that there is a great deal of variability between people with Parkinson’s in terms of things like their symptoms as well as their speed of progression. So much variability that researchers now believe that we may be dealing with a number of different conditions that all have the same sort of appearance as “Parkinson’s disease”, but they could have different underlying biology and causes.
This belief has led to numerous research efforts that are trying to tease out the different types of “Parkinson’s”, which will hopefully lead to more focused treatments in future.
In their study, the Sheffield & Oxford researchers investigated two aspects of the fibroblast cells function:
- Energy production (mitochondrial health)
- Waste disposal (or lysosomal function – click here to read a previous SoPD post on this topic)
Curiously, the researchers found little difference between the Parkinson’s fibroblasts and those collected from control participants in terms of these two aspects of cellular functioning. But they did note that there was a lot more variability within the Parkinson’s samples.
Important to our discussion in this post today, however, is that when the investigators treated some of the fibroblasts with UDCA, they observed that the treatment returned the Parkinson’s fibroblasts to a normal level of mitochondrial functioning – providing further support for the beneficial properties of UDCA.
Given all this research, the Parkinson’s research community have been keen to test UDCA evaluated in clinical trials for Parkinson’s.
Has anyone testing UDCA in the clinic for Parkinson’s?
A few years ago, there was a small Phase I clinical trial of UDCA in individuals with Parkinson’s conducted at the University of Minnesota – Clinical and Translational Science Institute.
The results of that study have been published:
Title: Pharmacokinetics, Safety, and Tolerability of Orally Administered Ursodeoxycholic Acid in Patients With Parkinson’s Disease-A Pilot Study.
Authors: Sathe AG, Tuite P, Chen C, Ma Y, Chen W, Cloyd J, Low WC, Steer CJ, Lee BY, Zhu XH, Coles LD.
Journal: J Clin Pharmacol. 2020 Jun;60(6):744-750.
PMID: 32052462 (This report is OPEN ACCESS if you would like to read it)
In this study, the researchers recruited 5 people with Parkinson’s and they conducted an open-label, multiple-ascending-dose study of oral UDCA (Click here to read more about this).
What does that mean?
‘Open-label’ refers to the fact that everyone involved in the study (participants and investigators) knew that they were receiving the treatment. This can introduce different levels of bias (such as investigator bias or placebo response in the participants), but given that this was the first time UDCA was being tested in Parkinson’s, safety was the primary consideration. ‘Multiple-ascending-dose’ refers to the participants being administered more than one dose, and those doses will be increasing as the study continues. And ‘oral UDCA’ refers to the fact that UDCA is a treatment taken orally.
The researchers also wanted to assess whether UDCA will increase levels of ATP in the brains of individuals with Parkinson’s.
What is ATP?
Adenosine Triphosphate (or ATP) is the unit of energy for your cells. It attaches to various proteins and ‘powers’ their function. It is produced by mitochondria converting nutrients (like glucose) from food into ATP.
A full explanation of the production of ATP is beyond the scope of this short post. To save space and time, I’m going to suggest you watch this video explainer of how mitochondria produce energy:
For those of you seeking more in-depth information of this process, I recommend watching this video:
The important detail here is that we require HUGE amounts of ATP in order to do everything we do at any moment of the day.
FUN FACT: The average human body produces/recycles its own weight in ATP…. every day!
In the Minnesota UDCA study, the researchers used a brain imaging technique called 31P-MRS to determine if UDCA increased levels of ATP levels in the brains of the participants.
And what on Earth is 31P-MRS?!?!?
31P-MRS (or 31phosphorous magnetic resonance spectroscopy) is a magnetic resonance-based form of imaging that is used to measure and quantify the function of the mitochondria.
Magnetic resonance imaging (MRI) is a type of diagnostic test that can create detailed images of nearly every structure and organ inside the body. MRI uses magnets and radio waves to produce images on a computer. While MRI allows for the identification of anatomical structures, MRS allows for the identification of chemical composition of brain tissue and in the case of the UDCA study: whether the drug successfully modulated the function of mitochondria in regions of the brain affected by Parkinson’s. For the participants in the study, the experience of 31P MRS will be exactly the same as having a normal MRI scan – you lie there in the machine thinking happy thoughts.
31P MRI-Spectroscopy. Source: PMC
In the Minnesota UDCA study, the participants were administered daily UDCA treatment for six weeks. And the dose that they were receiving gradually increased over time (from 15 mg/kg/day in week 1, to 50 mg/kg/day from week 3 to week 6).
The researchers found that these doses were safe and generally well tolerated. The treatment also resulted in modest increases in ATP levels (based on brain imaging technique called 31P-MRS).
Clinical assessments suggested possible improvements in Parkinson’s symptoms (using the Unified Parkinson’s Disease Rating Scale (UPDRS) parts I-IV), but the investigators were quick to point out in their report that the study was small and open label, which could lead to “placebo responses”. So the clinical results must be taken with a grain of salt. But the researchers suggested that based on the results of the study “a larger double-blind clinical trial is now warranted“.
And a larger double-blind clinical study is where we come back to the research team at Sheffield University.
Starting in January 2019, they started recruiting participants in a clinical trial, known as the “UP Study” (“UDCA in Parkinson’s”). The study was conducted at two research centres in the UK – one in Sheffield and one in London. The main investigational team is in Sheffield – led by Prof Oliver Bandmann – and they are working in collaboration with Prof Tom Foltynie and his team at University College London Hospitals.
And before we go any further – for the purpose of full disclosure, I need to say that Cure Parkinson’s was a funder of the UP study. The author of this blog is the director of research at Cure Parkinson’s so he may be a little biased in his interpretations/descriptions of the results.
Recently they published the results of the study:
Title: A Double-Blind, Randomized, Placebo-Controlled Trial of Ursodeoxycholic Acid (UDCA) in Parkinson’s Disease.
Authors: Payne T, Appleby M, Buckley E, van Gelder LMA, Mullish BH, Sassani M, Dunning MJ, Hernandez D, Scholz SW, McNeill A, Libri V, Moll S, Marchesi JR, Taylor R, Su L, Mazzà C, Jenkins TM, Foltynie T, Bandmann O.
Journal: Mov Disord. 2023 May 29. Online ahead of print.
PMID: 37246815 (This report is OPEN ACCESS if you would like to read it)
The study – involving 30 participants who are less than 3 years since diagnosis – was a Phase II, placebo controlled, double blind, randomised clinical trial assessing the longer-term safety and tolerability of 30 mg/kg daily dosing of UDCA in people with Parkinson’s.
The participants were randomly assigned (in a 2:1 ratio) to receive either UDCA or a placebo, for a total of 48 weeks. The primary outcome measures of the study were the safety and tolerability of UDCA in Parkinson’s at a dose of 30 mg/kg (which is within the dose range tested in the 6 week Minnesota UDCA study mentioned above) over a longer period of time. Additional clinical and biological endpoints are also being explored (Click here to read more about the details of the study).
After 48 weeks of treatment, the investigators found that (like the Minnesota UDCA study) UDCA was safe and well tolerated at the dose tested. The most frequently reported complaint in the UDCA treatment group was mild transient gastrointestinal issues, which is pretty good by clinical trial standards.
Did the UDCA treatment slow the progression of Parkinson’s?
Well, the UP study wasn’t really powered to determine this (with only 30 individuals involved in the study). A clear test of efficacy will require a much larger study involving a lot more participants.
But the researchers did record clinical symptoms, didn’t they?
Yes they did.
And interestingly, the researchers did see improvements in the clinical motor symptoms of Parkinson’s when they were measured by the clinician-based Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), but these improvements were observed in both the UDCA and placebo treated groups.
In their exploratory measures of gait using much more sensitive wearable sensors, the researchers did see difference between the UDCA treated group and the placebo group.
The investigators reported that cadence (or the number of steps per minute) increased in the UDCA group (but decreased in the placebo group) between baseline assessments and the final assessment at 48 weeks. In the graph below, you will see that most of the placebo group (on the left) experienced a reduction in their number of steps, while many in the UDCA group (on the right) presented an increase in the number of steps:
In addition to this encouraging result, the MRS results indicated improvements in different aspects of mitochondrial functioning:
The researchers concluded their write up of the UP study results by saying “the excellent safety profile of UDCA at 30 mg/kg, combined with the 31P-MRS-based evidence of target engagement and the promising results from the gait analysis, provide strong rationale for future trials of UDCA in Parkinson’s“. And they are now working on a larger clinical trial for testing the efficacy of UDCA in Parkinson’s.
Interesting. So what does it all mean?
Before we sum up, there is one other interesting detail to this research that should be mentioned.
In late 2022, Prof Mortiboys and colleagues published this report:
Title: 3α,7-Dihydroxy-14(13→12)abeo-5β,12α(H),13β(H)-cholan-24-oic Acids Display Neuroprotective Properties in Common Forms of Parkinson’s Disease.
Authors: Luxenburger A, Clemmens H, Hastings C, Harris LD, Ure EM, Cameron SA, Aasly J, Bandmann O, Weymouth-Wilson A, Furneaux RH, Mortiboys H.
Journal: Biomolecules. 2022 Dec 30;13(1):76.
PMID: 36671460 (This report is OPEN ACCESS if you would like to read it)
In this study, the researchers reported the discovery and synthesis of novel bile acid derivatives (similar to UDCA) and they evaluated their biological activity in cell cultures of fibroblasts from patients with either idiopathic/sporadic or LRRK2-associated Parkinson’s.
This work involved a collaboration with a biotech company called ICE Pharma – which is a global leader in bile acid products.
The research team reported on a number of molecules (code named with numbers) that boosted mitochondrial function to a similar level or above that of UDCA in many of the tests that they used, particularly in the context of LRRK2 genetic variants (“Of particular interest is that all the novel bile acid analogues were more efficacious than UDCA when tested in the more homogeneous LRRK2G2019S patient fibroblasts“).
Further research in models of Parkinson’s is required for these novel molecules before they can be tested clinically, but it is encouraging that biotech companies are exploring this field.
So what does it all mean?
UDCA is a bile acid that was identified in a drug screening study as exhibited some interesting properties in models of Parkinson’s. This research has led to clinical trials which have provided supportive data that warrants further investigation in larger studies of efficacy in Parkinson’s.
It is interesting to note that last year a closely related molecule (TUDCA or tauroursodeoxycholic acid, which is basically UDCA with taurine attached to it) was approved for the treatment of Amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease or motor neurone disease) by the US FDA (Source). The approved agent, called Relyvrio, is a combination therapy (phenylbutyrate and TUDCA) that has been developed by a biotech company called Amylyx Pharmaceuticals.
Relyvrio is now being clinically tested in a Phase 2 clinical trial of Alzheimer’s. The “Pegasus trial” is a 24-week, randomized, double-blind, placebo-controlled study involving 96 people with early Alzheimer’s (Click here to read more about this study). It is really interesting that so much research and biotech interest is focused on this area of biology and its potential in neurodegenerative conditions. It suggests positive developments may lie ahead for the field.
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EDITOR’S NOTE: The writer of this post is the director of research at Cure Parkinson’s which was a funder of the ‘UP study’ (UDCA in Parkinson’s clinical trial) that was conducted in Sheffield, and thus he may be biased in any opinions or comments shared. Cure Parkinson’s has not requested the production of this material, nor have the investigators mentioned been asked for comment or agreement on the text. The author has written this post solely on the basis that he thought the content would be of interest to the Parkinson’s community.
The information provided by the SoPD website is for information and educational purposes only. Under no circumstances should it ever be considered medical or actionable advice. It is provided by research scientists, not medical practitioners. Any actions taken – based on what has been read on the website – are the sole responsibility of the reader. Any actions being contemplated by readers should firstly be discussed with a qualified healthcare professional who is aware of your medical history. While some of the information discussed in this post may cause concern, please speak with your medical physician before attempting any change in an existing treatment regime.
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